Dr Michi Yukawa completed her geriatric fellowship at the University of Washington (UW) in June 2000, and she is an Acting Instructor within the Division of Gerontology and Geriatric Medicine (DGGM) at the UW. Prior to her geriatric fellowship, she practiced in Boston MA for five years as an internist. The K-23 Award will give Dr Yukawa time and resources to acquire knowledge and technical skills to become an independent physician scientist. Dr Itamar B Abrass will guide her career development within Geriatric Medicine. Dr D Scott Weigle will be her research mentor and supervise her laboratory work and development of research protocols. Additional faculty members in the DGGM and the Department of Endocrinology of the UW will provide further guidance. She will attend advanced classes in biostatistics at the School of Public Health of the UW. Controlled dietary intervention and physiologic studies will be performed at the Clinical Research Center (CRC) of the University of Washington Medical Center (UWMC). The long-term objective of her research is to determine the underlying pathophysiology of involuntary weight loss and anorexia in the geriatric population. Understanding energy regulation and metabolism in healthy older adults is necessary prior to investigating older adults with involuntary weight loss and anorexia. Previous studies have reported dysregulation of energy intake in older subjects after calorie restriction. Other studies have suggested abnormalities in leptin homeostasis in older adults. Therefore, the specific aims of the proposed project are to test the hypothesis that elevated pro-inflammatory cytokines lead to elevated leptin levels in older adults, which in turn are associated with inability of older adults to recover after a period of moderate caloric restriction. 1) A cross-sectional comparison of healthy community dwelling older and younger adults before and after calorie restriction will be performed. 2) The same cohort of older subjects will be followed for two years to identify factors that predict weight loss in older adults. [3) The relationship between pro-inflammatory cytokines, leptin levels and involuntary weight loss in older adults will be investigated. Pro-inflammatory cytokines secreted from adipocytes of older adults with and without weight loss and healthy younger subjects will be compared. Leptin levels in culture media will be analyzed by radioimmunoassay, and leptin mRNA in adipocytes will be analyzed by real time RT-PCR. The goal of these studies is to define the relationship of pro-inflamlnatory cytokines and leptin levels to body weight regulation in older adults.]